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An 86-year-old Caucasian man had prior episodes of fever (up to 38 °C), mild abdominal pain, tachycardia, and malaise in the last 3 months, lasting 2–3 days. He never suffered from abdominal or chest pain, rash, or arthralgia. Major causes of fever were excluded (pulmonary, urinary, abdomen, skin infections, neoplasms, and major rheumatologic disorders). The patient was native of Altamura with a family history of familial Mediterranean fever (FMF). The genetic testing confirmed the presence of MEFV gene variants c.442G>C (E148Q) on exon 2 and c.2282G>A (R761H) on exon 10, all in heterozygosity. Mildly elevated serum transaminases suggested an ongoing form of FMF hepatitis on nonalcoholic liver steatosis. The patient started colchicine 1 mg/day that induced symptom control and normalization of inflammatory markers, hyperbilirubinemia, and markers of cholestasis. Symptoms of FMF can appear at any age in life and our patient represents a very late-onset clinical case. The Apulian region has a consistent clustering of MEFV variants and FMF families with affected individuals in multiple consecutive generations. Families show unique clinical features and rare signs of secondary amyloidosis without kidney damage. Genetic and environmental bases of this phenotypic variant are under scrutiny. Colchicine lifetime remains the mainstay of treatment in FMF patients. • Familial Mediterranean fever (FMF) is the most frequent hereditary monogenic recurrent fever syndrome, and symptoms can appear at any age in life. • Late-onset FMF approaches 30% in late adulthood, but in general, onset of FMF after the age of 40 (late onset FMF) is rare, usually associated with M694V heterozygosity. • In a local cluster of FMF families (Altamura, Puglia, Southern Italy), we report a very late-onset FMF (variants E148Q, R761H) in an 86-year-old patient with a positive family history of FMF in two generations of descendants. • While lifetime colchicine remains the mainstay of treatment in FMF patients, prospective studies need to identify the characteristics of several phenotypic variants accounting for (very)-late onset FMF.

Simple Summary Selective neck dissection is currently accepted as the standard of care for lateral cervical nodal disease from papillary thyroid cancer. However, the clinical intraoperative detection of metastatic nodal involvement may be challenging, especially in difficult-to-spot neck levels behind the sternocleidomastoid muscle, and hinges on imaging investigations. In this respect, the significance of diagnostic intraoperative US in metastatic papillary thyroid cancer seems to be under-investigated in literature. We ran a prospective diagnostic study where an intraoperative ultrasound (IOUS) showed increased sensitivity for the detection of lateral neck nodes with respect to preoperative US scans, especially in the difficult-to-spot neck levels: in sublevels such as IIb and V, up to one quarter of patients examined had nodes newly detected by IOUS that were confirmed at pathology. This study offers evidence that IOUS may provide accurate intraoperative node mapping, supporting precise and more reliable selective neck dissection. Abstract (1) Background: Lymph node metastases from papillary thyroid cancer (PTC) are frequent. Selective neck dissection (SND) is indicated in PTC with clinical or imaging evidence of lateral neck nodal disease. Both preoperative ultrasound (PreUS) and intraoperative palpation or visualization may underestimate actual lateral neck nodal involvement, particularly for lymph-nodes located behind the sternocleidomastoid muscle, where dissection may also potentially increase the risk of postoperative complications. The significance of diagnostic IOUS in metastatic PTC is under-investigated. (2) Methods: We designed a prospective diagnostic study to assess the diagnostic accuracy of IOUS compared to PreUS in detecting metastatic lateral neck lymph nodes from PTC during SND. (3) Results: There were 33 patients with preoperative evidence of lateral neck nodal involvement from PTC based on PreUS and fine-needle cytology. In these patients, IOUS guided the excision of additional nodal compartments that were not predicted by PreUS in nine (27.2%) cases, of which eight (24.2%) proved to harbor positive nodes at pathology. The detection of levels IIb and V increased, respectively, from 9% (PreUS) to 21% (IOUS) (p < 0.0001) and from 15% to 24% (p = 0.006). (4) Conclusions: In the context of this study, IOUS showed higher sensitivity and specificity than PreUS scans in detecting metastatic lateral cervical nodes. This study showed that IOUS may enable precise SND to achieve oncological radicality, limiting postoperative morbidity.

An 86-year-old Caucasian man had prior episodes of fever (up to 38 °C), mild abdominal pain, tachycardia, and malaise in the last 3 months, lasting 2-3 days. He never suffered from abdominal or chest pain, rash, or arthralgia. Major causes of fever were excluded (pulmonary, urinary, abdomen, skin infections, neoplasms, and major rheumatologic disorders). The patient was native of Altamura with a family history of familial Mediterranean fever (FMF). The genetic testing confirmed the presence of MEFV gene variants c.442GC (E148Q) on exon 2 and c.2282GA (R761H) on exon 10, all in heterozygosity. Mildly elevated serum transaminases suggested an ongoing form of FMF hepatitis on nonalcoholic liver steatosis. The patient started colchicine 1 mg/day that induced symptom control and normalization of inflammatory markers, hyperbilirubinemia, and markers of cholestasis. Symptoms of FMF can appear at any age in life and our patient represents a very late-onset clinical case. The Apulian region has a consistent clustering of MEFV variants and FMF families with affected individuals in multiple consecutive generations. Families show unique clinical features and rare signs of secondary amyloidosis without kidney damage. Genetic and environmental bases of this phenotypic variant are under scrutiny. Colchicine lifetime remains the mainstay of treatment in FMF patients. KEY POINTS: • Familial Mediterranean fever (FMF) is the most frequent hereditary monogenic recurrent fever syndrome, and symptoms can appear at any age in life. • Late-onset FMF approaches 30% in late adulthood, but in general, onset of FMF after the age of 40 (late onset FMF) is rare, usually associated with M694V heterozygosity. • In a local cluster of FMF families (Altamura, Puglia, Southern Italy), we report a very late-onset FMF (variants E148Q, R761H) in an 86-year-old patient with a positive family history of FMF in two generations of descendants. • While lifetime colchicine remains the mainstay of treatment in FMF patients, prospective studies need to identify the characteristics of several phenotypic variants accounting for (very)-late onset FMF.

The aim of this retrospective multicenter study was to verify whether the substernal goiter and the type of surgical access could be risk factors for recurrent laryngeal nerve palsy during total thyroidectomy. Between 1999-2008, 14,993 patients underwent total thyroidectomy. Patients were divided into three groups: group A (control; n=14.200, 94.7%), cervical goiters treated through collar incision; group B (n=743, 5.0%) substernal goiters treated by cervical approach; group C (n=50, 0.3%) in which a manubriotomy was performed. Transient and permanent unilateral palsy occurred significantly more frequently in B+C vs. A (P≤.001) and in B vs. A (P≤.001). Transient bilateral palsy was significantly more frequent in B+C vs. A (P≤.043) and in C vs. A (P≤.016). Permanent bilateral palsy was significantly more frequent in B+C vs. A (P≤.041), and in B vs. A (P≤.037). Extension of the goiter into the mediastinum was associated to increased risk of recurrent nerve palsy during total thyroidectomy.

Resume L’objectif de cette etude etait d’evaluer l’extension mediastinale du goitre en tant que facteur de risque de paralysie recurrentielle apres thyroidectomie. Une thyroidectomie totale etait realisee chez 14 993 patients entre 1999 et 2008. Trois groupes de patients etaient identifies : le groupe A (temoins ; n = 14 200 ; 94,7 %), goitre cervical traite par incision horizontale ; le groupe B ( n = 743 ; 5,0 %) goitre sous-sternal traite par voie cervicale ; le groupe C ( n = 50 ; 0,3 %) avec manubriotomie. L’incidence des formes transitoire et permanente de paralysie recurrentielle unilaterale etait augmentee dans les groupes B + C compares au groupe A ( p p p p

In some tumors, psychosocial interventions may enhance health-related quality of life (HRQOL) of patients. The effects of psychological variables on HRQOL in hepatocellular carcinoma (HCC) patients have been rarely assessed. The aim of this work is to evaluate the psychopathological profile of HCC and cirrhotic patients and its effect on HRQOL. Twenty-four HCC patients (median age 71, Child A 21, Child B 3), 22 cirrhotic patients (median age 68, Child A 20, Child B 2) and 20 control subjects were included in this study. Each subject completes four questionnaires: medical outcomes study short form-36 (SF-36, HRQOL evaluation); Hamilton-D (quantitative evaluation of depression; positive ≥8); symptom check list 90-revised (SCL 90-R, general psychopathological profile; nine domains, each positive >1); Toronto alexithymia scale (TAS 20) (positive ≥60). SCL 90-R: cirrhotic patients differ from HCC subjects for somatization (SOM) (M ± SD 1.09 ± 0.6 vs 0.65 ± 0.6; p = 0.01) and anxiety (M ± SD 0.85 ± 0.46 vs 0.58 ± 0.38; p = 0.01) items. TAS 20: positive in 50% of HCC patients, in 54% of cirrhotic patients (p = n.s.) and in none of controls. Hamilton-D: higher scores in cirrhotic patients than in the HCC group (86 vs 46%; p = 0.005). SF-36: each item, except bodily pain, is lower in both group of patients in comparison with controls. Pearson correlation analysis shows negative correlations on HRQOL of depression, SOM and anxiety both in cirrhotic and HCC subjects, also of obsessive-compulsive and hostility items in HCC. This is the first report on the psychopathological profile of HCC patients: the results open questions on the role of psychological interventions that may improve HRQOL of patients before treatment and in the follow-up.

Objectives: The existence of specific features of Metabolic Syndrome (MetS) in psychiatric population in comparison to not psychiatric patients has not been systematically investigated. The purpose of this study is to evaluate the differences of MetS among a group of psychiatric patients and a group of internal medicine patients in terms of anthropometric measurements, biochemical variables, and cardiovascular risk. Methods: We enrolled 83 psychiatric inpatients under pharmacological treatment (schizophrenia n = 24, bipolar disorder n = 27, major depression n = 14, other n = 18) and 77 internal medicine patients visited for supposed MetS as affected by overweight or arterial hypertension. Results: Psychiatric patients differed from control subjects by age (yrs) (47 ± 9 vs. 52 ± 8.6, p = 0.001), waist circumference (cm) (111.9 ± 10.9 vs. 106 ± 12.6, p= 0.02), HDL cholesterol (mg/dl) (36.8 ± 7 vs. 48 ± 11.3, p = 0.001), serum insulin (µU/ml) (26 ± 12.5 vs. 16.4 ± 8.8, p = 0.001), triglyceride/HDL cholesterol ratio (4.8 ± 2.7 vs. 3.3 ± 2.2, p = 0.01). Female psychiatric patients had higher levels of triglycerides (mg) (178 + 86 vs. 115 + 53, p = 0.002) and of HOMA index (7.8 + 5 vs. 3.8 + 3.3, p = 0.005). Triglycerides and triglycerides/HDL ratio levels were higher in Unipolar Depression. A positive association was found between antidepressant drug treatment with triglycerides and triglycerides/HDL ratio levels, neuroleptic treatment with the HOMA index, and antipsychotics drugs with the Framingham index. Limitations: Psychiatric study population numerosity and duration of psychiatric illness and drug treatment. Conclusions: Specific features of MetS in psychiatric population are mainly represented by young age of onset, hyperinsulinemia, increased abdominal adiposity, and low HDL cholesterol whose common denominator may be insulin-resistance.

Little is known on hepatic function in patients with hepatocellular carcinoma (HCC). Metabolic changes were explored in HCC patients before/after nonsurgical therapy.HCV-related Child-Pugh A cirrhotic patients with (n = 37) or without HCC (n = 14) and healthy controls (n = 23) were enrolled. Subjects underwent breath testing with (13)C-methacetin or (13)C-ketoisocaproate for exploring microsomal and mitochondrial function, respectively. HCC patients repeated the tests 1-2, 30, and 180 d after radiofrequency ablation (n = 27, RFA) or transarterial chemoembolization (n = 10, TACE).At baseline, cirrhotic patients showed decreased methacetin demethylation capacity compared with controls (8.1 +/- 2.1 versus 13.7 +/- 1.3% cum. dose exhaled at 60 min, M +/- CI, P0.001) and minor changes in ketoisocaproate decarboxylation. HCC patients had methacetin demethylation comparable to cirrhotic subjects, but a significantly lower ketoisocaproate decarboxylation (8.5 +/- 1.0 versus 11.6 +/- 1.9% cum. dose exhaled at 60 min, P0.001). Methacetin metabolism was significantly decreased following TACE (-28%, P0.05) but not RFA. Ketoisocaproate decarboxylation was unaffected by TACE but decreased after RFA (-27%, P0.05). A recovery was noticed with ketoisocaproate as a probe after 1 and 6 mo (P0.003). HCC recurrence was associated with early decrease of ketoisocaproate decarboxylation.Liver mitochondrial function is decreased in cirrhotic patients with HCC suggesting a possible tumor-induced suppressant effect. RFA but not TACE appears to spare residual (microsomal) liver mass, but induces such a transient stunning effect on mitochondrial function. Improved mitochondrial function after 1 and 6 mo from RFA may represent an additional parameter of treatment efficacy. Breath test assessing liver function may have potential applications in HCC management.

When total thyroidectomy is performed for substernal goitre, a high risk of morbidity is reported. Advanced vessel sealing devices provide an alternative to the conventional clamp and tie technique. The aim of this study is to compare the outcome of patients who underwent total thyroidectomy for substernal goitre using Ligasure Small Jaw, Harmonic Focus, or conventional technique.Between 2011 and 2014, from a population of 393 patients undergoing surgery for thyroid disease, 75 (49 females, 26 males, mean age: 57.9 years; range: 28-83 years) underwent total thyroidectomy by the same surgeon for substernal goitre. Patients were divided into three groups: group A (n = 26) in which total thyroidectomy was performed using conventional technique; group B (n = 22), and group C (n = 27) in which total thyroidectomy was performed using Ligasure Small Jaw and Harmonic Focus, respectively. Operative time, time to drain removal, hospitalization and morbidity (hypoparathyroidism, vocal cord palsy, haemorrhage, seroma, other) were analyzed.Mean duration of surgery was 136.5 ± 26.7 min in group A vs 110.5 ± 24.8 in B, and 101.6 ± 25.4 in C, with significant statistical differences between A vs B (p 0.005) and C (p 0.0001). There was no mortality. The overall morbidity was 29.3%. There was no significant difference in time to drain removal, postoperative hospitalization, and morbidity among the three groups.This is the first study analyzing advanced vessel sealing devices in total thyroidectomy for substernal goitre in the literature. The use of advanced vessel sealing devices significantly reduces operative time of total thyroidectomy performed for substernal goitre but does not seem to affect the other evaluated outcomes.

Leakage of a large bowel anastomosis remains the most serious postoperative complication in gastrointestinal surgery. In a recent experimental study we found that surgically induced hypoxia resulted in more derangement of a variety of biochemical markers in the large bowel (LB) than in the small bowel (SB). We explored the question of whether spontaneous and agonist-induced contractility of SB and LB muscle strips was influenced by surgical procedures and how contractility was related to energetic oxidative metabolism capacity in smooth muscle mitochondria. Sixty male New Zealand rabbits were operated on under general anesthesia. Segments of ileum and colon were resected from each rabbit, and an end-to-end anastomosis was constructed. A representative subset of segments from SB (n = 14) and LB (n = 14) at time 0 was used as controls. Tracts containing an anastomosis were resected at days 2, 7, and 14 after operation. At each time point, 20 segments adjacent to the anastomosis of both SB and LB were used for tensiometric and biochemical studies. Tensiometric studies demonstrated modifications in the smooth muscle function at both the acute and chronic stages with intestinal inflammation that may contribute to surgical stress-associated abnormal motility. Biochemical data showed that the respiratory capacity of the resected LB was more impaired than that of the SB. In both SB and LB, changes in respiratory activity preceded tensiometric changes. Thus abnormalities of contractility after surgical stress are more evident in LB than SB in segments adjacent to the anastomoses. This could be the consequence of abnormal biochemical changes, as adenosine triphosphate (ATP) is required for membrane potential maintenance, calcium homeostasis, and actin-myosin interactions.

The American Association for the Study of Liver Diseases and the European Association for the Study of the Liver exclude any role of contrast-enhanced ultrasound (CEUS) in the diagnosis of hepatocellular carcinoma (HCC) while the Italian Association for the Study of the Liver suggests its use for larger HCC. This study evaluated the accuracy of CEUS in comparison with computed tomography (CT) in the diagnosis of HCC and of residual of HCC after treatment. We retrospectively evaluated 124 patients with 148 HCC nodules: 34 small (≤20 mm) and 114 large nodules (>20 mm). Ninety-three patients underwent treatment [one resection, 23 transcatheter arterial chemoembolisation (TACE), 37 radiofrequency ablation (RFA), 32 TACE/RFA combined with sorafenib]. The diagnosis of HCC on CEUS was confirmed by the typical pattern of arterial enhancement and portal and/or venous phase washout. We performed 90 CEUS for the initial diagnosis of HCC in 85 patients and 107 CEUS for the diagnosis of residual HCC after 1-month treatment in 92 patients. Sensitivity, specificity, positive predictive value, negative predictive value of CEUS and CT in the initial diagnosis of HCC were: 63 vs 92, 100 vs 100, 100 vs 100, 9 vs 25 for small HCC; 77 vs 92, 100 vs 100, 100 vs 100, 13 vs 22 for large HCC. In the diagnosis of residual of HCC, CEUS had a sensitivity of 70 % for small nodules and 76 % for large nodules, with an overall specificity of 100 %. CEUS is useful in the initial diagnosis and in the assessment of necrosis after RFA and TACE of HCC nodules.

Summary The interplay between contraction and relaxation in the gall-bladder muscularis leads to appropriate gall-bladder emptying and refilling during fasting and in the postprandial state in vivo. Several studies in both human and animal models have focused on cellular and molecular events in the gall-bladder wall in health and disease in vitro. Principal methods to study gall-bladder smooth muscle function include receptor binding studies (at the level of plasmamembranes or histological sections), phase contrast microscopy (at the level of isolated smooth muscle cells), and tensiometry (at the level of smooth muscle strips or the whole gall-bladder). At a very early stage, cholesterol gallstone disease is characterized by exposure of the gall-bladder wall to excess of biliary cholesterol and the cytotoxic effect of the bile salt deoxycholate. On a long-term basis, a form of gall-bladder leiomyopathy develops with defects involving the mechanisms of signal transduction at the level of plasmamembranes. The end-stage result is pathological contraction and/or relaxation of smooth musculature, impaired gall-bladder motility and gall-bladder stasis, all key factors in the pathogenesis of biliary cholesterol crystallization and gallstones.

Cholestasis is associated with systemic and hepatic oxidative and nitrosative stress; in this scenario, the conjugated hydrophilic bile salt ursodeoxycholate (UDCA) might play a protective role.Circulating oxidative and nitrosative stress markers were assessed in patients with primary biliary cirrhosis (PBC) before and during UDCA (15-20mg/kg/day) therapy.In patients with stage I-II PBC, UDCA improved ALT and alkaline phosphatase levels and near normalized serum thioredoxin (1.97 ± 0.37 vs 2.41 ± 0.39 nmol/L), nitrotyrosine (15 ± 4 vs 22 ± 7 nmol/L), nitrosothiols (144 ± 28 vs 205 ± 84 nmol/L) and K-18 levels (162 ± 21 vs 228 ± 33 U/L). Conversely, less marked changes were noted in patients with stages III-IV who showed lower thioredoxin (1.01 ± 0.31 nmol/L), higher nitrosothiols (605 ± 64 nmol/L), nitrotyrosine (62 ± 13 nmol/L) and K-18 levels (521 ± 57 U/L). Overall, thioredoxin was inversely related with nitrotyrosine (r=-0.838, P0.001) and K-18 (r=-0.838, P0.001) levels. Nitrosothiols and K-18 were linearly and significantly related with nitrotyrosine (r=0.862, P0.001; r=0.894, P0.001, respectively).Oxidative and nitrosative changes in patients with PBC are effectively counteracted by UDCA. The protective effect of UDCA, however, are limited to early disease stages and progressively diminishes with ongoing cholestasis.

Different nuclear genes are thought to be involved in the regulation of the complex phenotype of metabolic syndrome (MS) and their number is increasing. A mutation in mitochondrial DNA (mtDNA), T4291C in transfer RNA isoleucine (tRNAile), has been associated with MS in a large American family. In addition, a mtDNA T16189C variant, already known to be associated with insulin resistance and type 2 diabetes mellitus in Caucasians, seems to underlie susceptibility to MS in the Chinese population. Our aim was to verify the T4291C and T16189C variants in subjects affected by different phenotypes of MS.Seventy patients with MS and 35 healthy individuals were investigated for the presence of the mtDNA variants by polymerase chain reaction-restriction fragment length polymorphism analysis.The T4291C variant was absent in patients and in controls. The T16189C variant was more frequent in patients with MS than in control subjects (21.4% versus 5.7%, P0.04) and was associated with hypertension (P=0.01), waist circumference (P=0.02), body mass index (P=0.009), visceral fat thickness (P=0.04), homeostasis model assessment (P=0.03), and the number of MS diagnostic criteria (P=0.01).The mtDNA T16189C variant is associated with MS and its different clinical expressions. Prospective studies are warranted to establish the clinical relevance of this association.

The hemolysis of human erythrocytes can be proposed as a valuable in vitro model to study the interaction of different molecules with the plasma membrane: given its simplicity and versatility, this method provides a reliable tool to screen potentially damaging or protective compounds like drugs, nutrients and endogenous molecules, with relevance to the pathophysiology and treatment of human diseases.

Background/Purpose Studies of children with urinary flow impairment (UFI) at the ureteropelvic junction (UPJ) have revealed prestenotic, stenotic, and poststenotic histologic changes. Muscle function, however, has not been investigated. We therefore evaluated in vitro UPJ contractility by tensiometry in children with UFI. Methods Freshly excised UPJs from 11 children with UFI (6 functional, 5 obstructive) were each divided into 3 parallel, prestenotic, stenotic, and poststenotic rings, and those from 7 children with Wilms' tumor were divided into proximal, medial, and distal segments. Each ring was studied in vitro by tensiometry in the basal state and after stimulation with 25 and 60 mmol/L KCl. Results The stenotic rings from the UFI subjects displayed a significantly lower basal contractility than the other 2 rings, and their 25 and 60 mmol/L KCl–induced contractility was absent or severely reduced, whereas the values of these parameters were similar to that observed in controls in the other 2 rings of patients with either functional or obstructive UFI. Conclusions Basal and KCl-induced contractility of the stenotic segment is severely impaired in children and infants with either functional or obstructive UFI, whereas the contractility of their pre- and poststenotic UPJ segments is similar to that recorded in controls.

Previous studies on celiac patients demonstrated that exposure to gliadin alters the motility of the upper gastrointestinal tract, leading to increased acid reflux. No literature is available regarding the possible presence of specialized intestinal metaplasia of the esophagus as a consequence of chronic reflux in adult celiac patients. Our purpose was to evaluate endoscopically and histologically the esophagi of a group of untreated celiac patients. We studied 60 celiac patients, 13 men and 47 women (mean age, 40 +/- 14 [SD] years; range, 18-80 years), at their first endoscopy (following a normal diet). The distal esophagus was evaluated and multiple biopsies were taken. Hematoxylin-eosin and alcian blue stainings were performed. A group of nonceliac, age- and sex-matched patients was used as a control. We found intestinal metaplasia in the distal esophagus of 16 of 60 (26.6%) celiacs (mean age, 45 +/- 13 years; range, 27-75 years), in comparison with a control-group prevalence of 10.9% (OR, 3.9; 95% CI, 1.4-11.2%). Among the celiac group with metaplasia, only one patient had reflux-like symptoms. None had esophagitis. In conclusion, we observed an increased prevalence of esophageal metaplasia in patients with celiac disease. This finding could be the result of motor abnormalities leading to chronic acid reflux, combined with a mucosa which is sensitive to gliadin.